HRP20000255A2

HRP20000255A2 - Use of thiazolidinediones for the treatment of hyperglycaemia

Info

Publication number: HRP20000255A2
Application number: HR20000255A
Authority: HR
Inventors: Robin Edwin Buckingham; Stephen Alistair Smith
Original assignee: Smithkline Beecham Plc
Priority date: 1997-10-13
Filing date: 2000-05-02
Publication date: 2001-02-28
Also published as: IL135513A0; NO20001898L; SK5312000A3; EA200000419A1; HUP0003922A2; BG104404A; NZ503862A; OA11683A; TR200000958T2; CA2306086A1; CN1281359A; WO1999018943A1; EA002659B1; AP2000001787A0; GB9721693D0; PL339813A1; EP1023056A1; BR9815219A; NO20001898D0; JP2001519382A

Description

Ovaj izum se odnosi na novu metodu liječenja, posebice na metodu liječenja i/ili profilakse nekih, određenih hiperglikemija. This invention relates to a new method of treatment, in particular to a method of treatment and/or prophylaxis of certain hyperglycemias.

European Patent Application, broj publikacije 0,306,228 se odnosi na neke derivate tiazolidindiona za koje se otkrilo da imaju hipoglikemijsko i hipolipidemijsko djelovanje. Jedan poseban tiazolidindion pokazan u EP 0306228 je 5-[4-[2-(N-metil-N-(2-piridil)amino)etoksi]benzil]tiazolidin-2,4-dion (ovdje nadalje naznačen kao 'spoj(I)'). WO 94/05659 prikazuje neke soli spoja (I) uključujući maleatne soli. European Patent Application, publication number 0,306,228 relates to some thiazolidinedione derivatives which have been found to have hypoglycemic and hypolipidemic effects. One particular thiazolidinedione disclosed in EP 0306228 is 5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione (hereinafter referred to as 'compound (I )'). WO 94/05659 discloses some salts of compound (I) including maleate salts.

Spoj (I)je primjer iz razreda antihiperglikemijskih tvari poznatih kao "insulin sensitisers" (ili "tvari koje pospješuju djelovanje insulina"). Spoj (I)je osobit tiazolidindionski "insulin sensitiser". Compound (I) is an example from the class of antihyperglycemic substances known as "insulin sensitisers" (or "substances that enhance the action of insulin"). Compound (I) is a special thiazolidinedione "insulin sensitiser".

European Patent Applications, brojevi publikacija: 0008203, 0139421, 0032128,0428312,0489663,0155845, 0257781, 0208420, 0177353, 0319189, 0332331, 0332332, 0528734, 0508740; International Patent Application, brojevi publikacija: 92/18501, 93/02079,93/22445 i United States Patent. brojevi: 5104888 i 5478852, također pokazuju određene tiazolidindionske "insulin sensitiser-e". European Patent Applications, publication numbers: 0008203, 0139421, 0032128,0428312,0489663,0155845, 0257781, 0208420, 0177353, 0319189, 0332331, 0332332, 0528734, 05084; International Patent Application, publication numbers: 92/18501, 93/02079, 93/22445 and United States Patent. Nos.: 5104888 and 5478852, also disclose certain thiazolidinedione "insulin sensitisers".

Druge serije spojeva za koje se uopćeno smatra da imaju djelovanje "insulin sensitiser-a" su one tipizirane pomoću spojeva prikazanih u International Patent Applications, brojevi publikacija WO 93/21166 i WO 94/01420. Ovi spojevi se ovdje navode kao "aciklički inzulinski sensitiser-i". Drugi primjeri acikličkih inzulinskih sensitiser-a su oni pokazani u United States Patent broj 5232945 i International Patent Application, brojevi publikacija WO 92/03425 i WO 91/19702. Other series of compounds generally believed to have "insulin sensitiser" activity are those typified by the compounds disclosed in International Patent Applications, publication numbers WO 93/21166 and WO 94/01420. These compounds are referred to herein as "acyclic insulin sensitisers". Other examples of acyclic insulin sensitisers are those disclosed in United States Patent No. 5232945 and International Patent Application Publication Nos. WO 92/03425 and WO 91/19702.

Primjeri drugih inzulinskih sensitiser-a su oni pokazani u European Patent Application, broj publikacije 0533933, Japanese Patent Application, broj publikacije 05271204 i United State Patent broj 5264451. Examples of other insulin sensitisers are those disclosed in European Patent Application, Publication No. 0533933, Japanese Patent Application, Publication No. 05271204, and United State Patent No. 5264451.

Izvješće ekspertnog odbora za dijagnostiku i klasifikaciju dijabetesa melitusa (Diabetes Care, vol 20(7), 1997, 1183-1197) smatra daje dijabetes tip 2 karakteriziran razinom glukoze u plazmi na tašte od ≥ 126 mg /dl (gdje se na tašte definira kao ne uzimanje nikakvih kalorija kroz najmanje 8 sati). U istom izvješću se također opisuje kako se dijabetes obično pojavljuje u razdoblju od nekoliko godina što je karakterizirano porastom razine glikemije u serumu na tašte za razliku od razine koja se uopćeno smatra normalnom - razina glukoze u plazmi od približno 110 mg/dl - prema navedenim značajkama hiperglikemije čistog tip 2 dijabetesa. Izvješće se također odnosi na metaboličke stadije između normalne homeostaze glukoze i dijabetesa, uključujući oslabljenu toleranciju prema glukozi i smanjenu glukozu na tašte. The report of the expert committee for the diagnosis and classification of diabetes mellitus (Diabetes Care, vol 20(7), 1997, 1183-1197) considers that type 2 diabetes is characterized by a fasting plasma glucose level of ≥ 126 mg/dl (where fasting is defined as not consuming any calories for at least 8 hours). The same report also describes how diabetes usually appears over a period of several years and is characterized by a rise in serum glycemic levels in the mother-in-law as opposed to what is generally considered normal - a plasma glucose level of approximately 110 mg/dl - according to the features hyperglycemia of pure type 2 diabetes. The report also addresses the metabolic stages between normal glucose homeostasis and diabetes, including impaired glucose tolerance and reduced fasting glucose.

Iz EP 0306228 je poznato da je spoj 1 koristan u profilaksi hiperglikemije i stoga za liječenje smanjene tolerancije prema glukozi. Interantional Patent Application, broj publikacije WO 95/07694 također otkriva da se tiazolidindioni mogu koristiti u liječenju smanjene tolerancije prema glukozi da se spriječi ili uspori početak dijabetesa melitusa tip 2. Međutim, EP 0306228 i WO 95/07694 ne spominju liječenje bilo kojeg specifičnog raspona hiperglikemije. It is known from EP 0306228 that compound 1 is useful in the prophylaxis of hyperglycemia and therefore for the treatment of impaired glucose tolerance. International Patent Application, publication number WO 95/07694 also discloses that thiazolidinediones can be used in the treatment of impaired glucose tolerance to prevent or slow the onset of type 2 diabetes mellitus. However, EP 0306228 and WO 95/07694 do not mention the treatment of any specific range hyperglycemia.

Pokazano je da spoj (I) osigurava posebice koristan učinak na kontrolu glikemije u rasponu hiperglikemije od povišene normalne do 126 140 mg/dl, tako da odlaže ili sprječava dalje povišenje hiperglikemije. Compound (I) has been shown to provide a particularly beneficial effect on glycemic control in the range of hyperglycemia from elevated normal to 126,140 mg/dl, thus delaying or preventing further elevation of hyperglycemia.

U skladu s tim, izum osigurava metodu za liječenje hiperglikemije, posebice hiperglikemije na tašte, naznačenu time što je razina glukoze u plazmi u rasponu od povišene normalne do ≤ 126 mg/dl, i ta metoda obuhvaća primjenu učinkovite ne-toksične i farmaceutski prihvatljive količine insulin sensitiser-a, na sisavcu kojemu je potrebna. Accordingly, the invention provides a method for the treatment of hyperglycemia, particularly fasting hyperglycemia, characterized by a plasma glucose level ranging from elevated normal to ≤ 126 mg/dl, and this method comprises the administration of an effective non-toxic and pharmaceutically acceptable amount of an insulin sensitiser, in a mammal in need thereof.

U skladu s tim, ovaj izum osigurava metodu za poboljšanje kontrole glikemije u stanjima karakteriziranim hiperglikemijom, posebice hiperglikemijom na tašte, naznačenu time što se poboljšanje osigurava kod hiperglikemija naznačenim time što je razina glukoze u plazmi u rasponu od povišene normalne do ≤ 126 mg/dl, i tako odlaže ili sprječava dalje povišenje hiperglikemije, i ta metoda obuhvaća primjenu učinkovite ne-toksične i farmaceutski prihvatljive količine insulin sensitiser-a, na sisavcu kojemu je potrebna. Accordingly, the present invention provides a method for improving glycemic control in conditions characterized by hyperglycemia, particularly fasting hyperglycemia, characterized in that the improvement is provided in hyperglycemia characterized by a plasma glucose level ranging from elevated normal to ≤ 126 mg/dl , and thus delays or prevents further elevation of hyperglycemia, and the method comprises administering an effective non-toxic and pharmaceutically acceptable amount of an insulin sensitiser to a mammal in need thereof.

Još u slijedećem aspektu, izum osigurava metodu za profilaksu hiperglikemije, posebice hiperglikemije na tašte, naznačenu time što je razina glukoze u plazmi u rasponu od > 126 mg/dl, ta metoda obuhvaća primjenu učinkovite ne-toksične i farmaceutski prihvatljive količine insulin sensitiser-a, na sisavcu kojemu je potrebna. In a further aspect, the invention provides a method for the prophylaxis of hyperglycemia, especially fasting hyperglycemia, indicated by the fact that the plasma glucose level is in the range of > 126 mg/dl, this method includes the use of an effective non-toxic and pharmaceutically acceptable amount of insulin sensitiser , on a mammal that needs it.

Jedna posebna skupina stanja koja su ovdje definirana, dodatno karakterizirana kao hiperglikemija na tašte naznačena time što je razina glukoze u plazmi na tašte u rasponu od povišene normalne do ≤ 126 mg/dl se dalje označuje kao hiperglikemija naznačena time što je razina glukoze u plazmi nakon oralnog testa tolerancije glukoze u rasponu od <140 mg/dl. One particular group of conditions defined herein, further characterized as fasting hyperglycemia characterized by a fasting plasma glucose level ranging from elevated normal to ≤ 126 mg/dl is further characterized as hyperglycemia characterized by a plasma glucose level after oral glucose tolerance test in the range of <140 mg/dl.

Slijedeća skupina stanja koja se ovdje definiraju, dodatno karakterizirana kao hiperglikemija na tašte u rasponu od povišene normalne do manje od ≤ l26mg/dl se dalje označuje kao hiperglikemija naznačena time što je razina glukoze u plazmi nakon oralnog testa tolerancije glukoze u rasponu od 140 do < 200 mg/dl. The next group of conditions defined here, further characterized as fasting hyperglycemia in the range of elevated normal to less than ≤ 126mg/dl is further referred to as hyperglycemia indicated by a plasma glucose level after an oral glucose tolerance test in the range of 140 to < 200 mg/dl.

Prikladan insulin sensitiser je tiazolidindion insulin sensitiser. A suitable insulin sensitiser is a thiazolidinedione insulin sensitiser.

Prikladan tiazolidindionski insulin sensitiser je spoj (I), ili njegov tautomerni spoj, ili njegova farmaceutski prihvatljiva sol, ili njegov farmaceutski prihvatljiv solvat. A suitable thiazolidinedione insulin sensitiser is compound (I), or a tautomeric compound thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof.

Drugi prikladni tiazolidindionski insulin sensitiser-i uključuju (+)-5-[[4-[(3,4-dihidro-6-hidroksi-2,5,7,8-tetrametil-2H-l-benzopiran-2-il)metoksi]fenil]meti]-2,4-tiazolidindion (ili troglitazon), Other suitable thiazolidinedione insulin sensitizers include (+)-5-[[4-[(3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2-yl) methoxy]phenyl]methyl]-2,4-thiazolidinedione (or troglitazone),

5-[4-[(1-metilcikloheksil)metoksi]benzil]tiazolidin-2,4-dion (ili ciglitazon), 5-[4-[(1-methylcyclohexyl)methoxy]benzyl]thiazolidine-2,4-dione (or ciglitazone),

5-[4-[2-(5-etilpiridin-2-il)etoksi]-benzil]tiazolidin-2,4-dion (ili pioglitazon) ili 5-[4-[2-(5-ethylpyridin-2-yl)ethoxy]-benzyl]thiazolidine-2,4-dione (or pioglitazone) or

5-[2-benzil-2,3-dihidrobenzopiran)-5-ilmetil]tiazolidin-2,4-dion (ili englitazon). 5-[2-benzyl-2,3-dihydrobenzopyran)-5-ylmethyl]thiazolidin-2,4-dione (or englitazone).

U jednom posebnom aspektu, metoda obuhvaća primjenu 2 do 12 mg spoja (I), osobito kada se primjenjuje dnevno. In a particular aspect, the method comprises administering 2 to 12 mg of compound (I), particularly when administered daily.

Posebice metoda obuhvaća primjenu od 2 do 4, 4 do 8 ili 8 do 12 mg spoja (I) dnevno. In particular, the method comprises the application of 2 to 4, 4 to 8 or 8 to 12 mg of compound (I) per day.

Posebice, metoda obuhvaća primjenu od 2 do 4 mg spoja (I), osobito kada se primjenjuje dnevno. In particular, the method comprises the administration of 2 to 4 mg of compound (I), especially when administered daily.

Posebice, metoda obuhvaća primjenu od 4 do 8 mg, veću nego što je 4 na primjer 4.1, do 8 mg, spoja (I), posebice kada se primjenjuje dnevno. In particular, the method comprises the administration of 4 to 8 mg, greater than 4 for example 4.1, to 8 mg, of compound (I), especially when administered daily.

Posebice, metoda obuhvaća primjenu od 8 do 12 mg spoja (I), osobito kada se primjenjuje dnevno. In particular, the method comprises the administration of 8 to 12 mg of compound (I), especially when administered daily.

Poželjno, metoda obuhvaća primjenu od 2 mg spoja (I), osobito kada se primjenjuje dnevno. Preferably, the method comprises the administration of 2 mg of compound (I), particularly when administered daily.

Poželjno, metoda obuhvaća primjenu od 4 mg spoja (I), osobito kada se primjenjuje dnevno. Preferably, the method comprises the administration of 4 mg of compound (I), particularly when administered daily.

Poželjno, metoda obuhvaća primjenu od 8 mg spoja (I), osobito kada se primjenjuje dnevno. Preferably, the method comprises the administration of 8 mg of compound (I), particularly when administered daily.

Razumljivo je da se insulin sensitiser, kao što je spoj (I) primjenjuje u farmaceutski prihvatljivom obliku, uključujući farmaceutski prihvatljive derivate kao što su farmaceutski prihvatljive soli, esteri i njegovi solvati, koji su prikladni. It is understood that an insulin sensitiser such as compound (I) is administered in a pharmaceutically acceptable form, including pharmaceutically acceptable derivatives such as pharmaceutically acceptable salts, esters and solvates thereof, as appropriate.

Prikladni oblici farmaceutski prihvatljivih soli insulin sensitisera, kao što je spoj (I), uključuju one opisane u gore spomenutim patentima i aplikacijama patenata kao što je opisano u EP 0306228 i WO 94/05659 za spoj (I). Suitable forms of pharmaceutically acceptable salts of insulin sensitizers, such as compound (I), include those described in the above-mentioned patents and patent applications as described in EP 0306228 and WO 94/05659 for compound (I).

Poželjna farmaceutski prihvatljiva sol za spoj (I)je maleat. A preferred pharmaceutically acceptable salt of compound (I) is the maleate.

Prikladni farmaceutski prihvatljivi oblici solvata insulin sensitiser-a, kao što je spoj (I), uključuju one opisane u gore spomenutim patentima i aplikacijama patenata, kao što je u EP 0306228 i WO 94/05659 za spoj (I), osobito hidrati. Suitable pharmaceutically acceptable forms of solvates of insulin sensitisers, such as compound (I), include those described in the above-mentioned patents and patent applications, such as in EP 0306228 and WO 94/05659 for compound (I), especially hydrates.

Tiazolidindionski insulin sensitiser-i, kao što je spoj (I) ili njegova farmaceutski prihvatljiva sol, mogu se pripraviti uporabom poznatih metoda, na primjer onih opisanih u gore spomenutim patentima i aplikacijama patenata kao što su EP 0306228 i WO 94/05659 za spoj (I). Otkrića iz gore spomenutih patenata i aplikacija patenata, kao što su EP 0306228 i WO 94/05659 u ovdje uključena putem referenci. Thiazolidinedione insulin sensitisers, such as compound (I) or a pharmaceutically acceptable salt thereof, can be prepared using known methods, for example those described in the aforementioned patents and patent applications such as EP 0306228 and WO 94/05659 for compound ( AND). The disclosures from the aforementioned patents and patent applications, such as EP 0306228 and WO 94/05659 are incorporated herein by reference.

Tiazolidindionski insulin sensitiser-i kao što je spoj (I), mogu postojati u jednom od nekoliko tautomernih oblika, od kojih su svi ovdje uključeni ili kao samostalni tautomerni oblici ili kao njihove mješavine. Neki od insulin sensitiser-a, kao što je spoj (I), sadrže jedan ili više kiralnih ugljikovih atoma, i stoga mogu postojati u dva ili više stereoizomernih oblika. Svi takvi oblici su ovdje uključeni ili kao samostalni izomeri ili kao mješavine izomera, uključujući racemate. Thiazolidinedione insulin sensitisers such as compound (I) can exist in one of several tautomeric forms, all of which are included herein either as individual tautomeric forms or as mixtures thereof. Some of the insulin sensitisers, such as compound (I), contain one or more chiral carbon atoms, and therefore can exist in two or more stereoisomeric forms. All such forms are included herein either as individual isomers or as mixtures of isomers, including racemates.

Pojam "farmaceutski prihvatljiv" kako se ovdje koristi podrazumijeva humanu i veterinarsku uporabu: na primjer pojam "farmaceutski prihvatljiv" podrazumijeva veterinarski prihvatljiv spoj. The term "pharmaceutically acceptable" as used herein includes both human and veterinary use: for example, the term "pharmaceutically acceptable" includes a veterinary acceptable compound.

Kako se ovdje koristi oralni test tolerancije na glukozu je onaj koji se navodi u Diabetes Care vol 20 (7), 1997, 1183-1197. The oral glucose tolerance test used herein is that reported in Diabetes Care vol 20 (7), 1997, 1183-1197.

Kako se ovdje koristi "povišena normalna" hiperglikemija treba ju shvatiti kao uopćeno razumljivu u struci, sa referencom na primjer u Report of the Expert Committee of the Diagnosis and Classification of Diabetes Mellitus ali se obično uzima u značenju glikemije naznačene time što je razina glukoze u plazmi >110 mg/dl. As "elevated normal" hyperglycemia is used here, it should be understood as generally understood in the art, with reference to, for example, the Report of the Expert Committee of the Diagnosis and Classification of Diabetes Mellitus, but it is usually taken to mean glycemia indicated by the fact that the glucose level in plasma >110 mg/dl.

U metodi ovog izuma aktivne tvari se poželjno primjenjuju u obliku farmaceutskih pripravaka. Kao što je gore pokazano, takvi pripravci mogu uključivati oba medikamenta ili samo jednog od njih. In the method of the present invention, the active substances are preferably applied in the form of pharmaceutical preparations. As indicated above, such compositions may include both drugs or only one of them.

Takvi pripravci mogu se spravljati miješanjem insulin sensitiser-a kao što je spoj (I) i osobito u količini od 2 do 12 mg spoja (I), i njegovog farmaceutski prihvatljivog nosača. Such preparations can be made by mixing an insulin sensitiser such as compound (I) and especially in an amount of 2 to 12 mg of compound (I), and its pharmaceutically acceptable carrier.

Uobičajeno su pripravci prilagođeni za oralnu primjenu. Međutim, mogu se prilagoditi i drugim oblicima primjene, na primjer parenteralnoj primjeni, sublingvalnoj ili transdermalnoj primjeni. Usually, preparations are adapted for oral administration. However, they can also be adapted to other forms of administration, for example parenteral administration, sublingual or transdermal administration.

Pripravci mogu biti u obliku tableta, kapsula, praha, granula, lozenga, supozitorija, praha za rekonstituciju, ili tekućih pripravaka, kao što su oralne ili sterilne parenteralne otopine ili suspenzije. The preparations may be in the form of tablets, capsules, powders, granules, lozenges, suppositories, powders for reconstitution, or liquid preparations, such as oral or sterile parenteral solutions or suspensions.

Da se dobije konzistencija za primjenu poželjno je da pripravak iz ovog izuma bude u obliku jedinične doze. In order to obtain a consistency for use, it is preferable that the preparation of this invention be in the form of a unit dose.

Oblici jedinične doze za oralnu primjenu mogu biti tablete i kapsule i mogu sadržavati uobičajene ekscipijente kao što su tvari za vezivanje, na primjer sirup, akacija, želatina, sorbitol, tragakant, ili polivinilpirolidon; tvari za punjenje, na primjer laktozu, šećer, kukuruzni škrob, kalcij fosfat, sorbitol ili glicin; lubrikante za spravljanje tableta, na primjer magnezij stearat; tvari za disintegraciju, na primjer škrob, polivinilpirolidon, natrijev škrobni glikolat ili mikrokristalnu celulozu; ili farmaceutski prihvatljive tvari za vlaženje kao što je natrijev lauril sulfat. Unit dosage forms for oral administration may be tablets and capsules and may contain conventional excipients such as binding agents, for example syrup, acacia, gelatin, sorbitol, tragacanth, or polyvinylpyrrolidone; fillers, for example lactose, sugar, corn starch, calcium phosphate, sorbitol or glycine; tableting lubricants, for example magnesium stearate; disintegrants, for example starch, polyvinylpyrrolidone, sodium starch glycolate or microcrystalline cellulose; or pharmaceutically acceptable humectants such as sodium lauryl sulfate.

Pripravci su poželjno u obliku jedinične doze u količini koja je prikladna za odgovarajuću dnevnu dozu. The preparations are preferably in the form of a unit dose in an amount suitable for the corresponding daily dose.

Prikladne doze za insulin sensitiser-e uključuju one koje su prikazane u gore spomenutim patentima i aplikacijama patenata. Suitable dosages for insulin sensitisers include those disclosed in the aforementioned patents and patent applications.

Prikladne doze, uključujući jedinične doze, spoja (I) sadrže 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 i 12 mg spoja (I). Suitable doses, including unit doses, of compound (I) contain 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12 mg of compound (I).

U liječenju koje sadrži druge pripravke osim spoja (I), potrebne doze i oblici primjene su uopćeno kao što je opisano u gore spomenutim publikacijama patenata koje su kao što se gore navodi ovdje uključene putem reference. Jedan primjer uključuje primjenu od 200 - 800 mg troglitazona, na primjer 200, 300 ili 400 mg. In a treatment containing preparations other than compound (I), the necessary dosages and forms of administration are generally as described in the above-mentioned patent publications, which are incorporated herein by reference as indicated above. One example involves the administration of 200-800 mg of troglitazone, for example 200, 300 or 400 mg.

Za vrijeme liječenja medikamenti se mogu primijeniti od 1 do 6 puta dnevno, ali najpoželjnije je 1 ili 2 puta na dan. During treatment, medications can be applied from 1 to 6 times a day, but 1 or 2 times a day is most preferable.

Čvrsti oralni pripravci mogu se pripremiti pomoću konvencionalnih metoda za miješanje, punjenje i spravljanje tableta. Ponavljana miješanja mogu se koristiti za raspodjelu aktivne tvari u onim pripravcima koji koriste velike količine tvari za punjenje. Takvi zahvati su naravno uobičajeni u struci. Tablete mogu biti obavijene u skladu sa metodama koje su dobro poznate u normalnoj farmaceutskoj praksi, posebice kod enteralnog obavijanja. Solid oral preparations can be prepared using conventional mixing, filling and tabletting methods. Repeated mixing can be used to distribute the active ingredient in those preparations that use large amounts of filler. Such procedures are of course common in the profession. Tablets may be coated according to methods well known in normal pharmaceutical practice, particularly enteral coating.

Oralni tekući pripravci mogu biti u obliku, na primjer, emulzija, sirupa ili eliksira, ili mogu biti predstavljeni kao suhi proizvodi za rekonstituciju sa vodom ili drugim prikladnim vehikulumom prije uporabe. Takvi tekući pripravci mogu sadržavati uobičajene dodatke kao što su suspendirajuće tvari, na primjer sorbitol, sirup, metil celuloza, želatina, hidroksietilceluloza, karboksimetilceluloza, gel aluminij stearata, hidrogenizirane jestive masti; emulgirajuće tvari, na primjer lecitin, sorbitan monooleat, ili akaciju; ne - vodene vehikulume (koji mogu uključivati jestiva ulja) na primjer bademovo ulje, frakcionirano kokosovo ulje, uljne estere kao što su esteri glicerina, propilen glikol, ili etilni alkohol, prezervative, na primjer metil ili propil p-hidroksibenzoat ili sorbičnu kiselinu; i ako se želi uobičajene tvari za poboljšanje okusa ili za bojanje. Oral liquid preparations may be in the form of, for example, emulsions, syrups or elixirs, or may be presented as dry products for reconstitution with water or other suitable vehicle prior to use. Such liquid preparations may contain conventional additives such as suspending agents, for example sorbitol, syrup, methyl cellulose, gelatin, hydroxyethyl cellulose, carboxymethyl cellulose, aluminum stearate gel, hydrogenated edible fats; emulsifying agents, for example lecithin, sorbitan monooleate, or acacia; non-aqueous vehicles (which may include edible oils) for example almond oil, fractionated coconut oil, oil esters such as glycerin esters, propylene glycol, or ethyl alcohol, preservatives, for example methyl or propyl p-hydroxybenzoate or sorbic acid; and if desired the usual substances for improving taste or for coloring.

Za parenteralnu primjenu, oblici tekuće jedinične doze se pripremaju uporabom spoja i sterilnog vehikuluma., i, ovisno o upotrijebljenoj koncentraciji, mogu biti ili suspendirani ili otopljeni u vehikulumu. Kod spravljanja otopina spoj se može otopiti u vodi za injekcije i sterilizirati pomoću filtra prije punjenja u prikladne ampule ili bočice i zatvaranja. Prednost je da se adjuvansi kao što je lokalni anestetik, prezervativ i puferske tvari mogu otopiti u vehikulumu. Da se poboljša stabilnost, pripravak se može smrznuti nakon punjenja u bočice i voda odstraniti pod vacuum-om. Parenteralne suspenzije se spravljaju na potpuno isti način, osim što se spoj (I) suspendira u vehikulumu umjesto da se otapa, i sterilizacija se ne može postići putem filtracije. Spoj se može sterilizirati izlaganjem etilen oksidu prije suspendiranja u sterilne posude. Prednost je da je surfaktant ili tvar za vlaženje uključena u pripravak da se olakša jednolika raspodjela spoja. For parenteral administration, liquid unit dosage forms are prepared using the compound and a sterile vehicle, and, depending on the concentration used, may be either suspended or dissolved in the vehicle. When making solutions, the compound can be dissolved in water for injection and sterilized using a filter before filling into suitable ampoules or vials and sealing. An advantage is that adjuvants such as local anesthetic, preservative and buffering substances can be dissolved in the vehicle. To improve stability, the preparation can be frozen after bottling and the water removed under vacuum. Parenteral suspensions are prepared in exactly the same way, except that compound (I) is suspended in a vehicle instead of being dissolved, and sterilization cannot be achieved by filtration. The compound can be sterilized by exposure to ethylene oxide before suspending in sterile containers. Advantageously, a surfactant or wetting agent is included in the composition to facilitate uniform distribution of the compound.

Pripravci mogu sadržavati od 0.1% do 99% težine, poželjno od 10 - 60% težine, aktivne tvari, ovisno o metodi primjene. Preparations can contain from 0.1% to 99% by weight, preferably from 10 - 60% by weight, of active substances, depending on the method of application.

Pripravak može, ako se želi, biti u obliku pakovanja koje je popraćeno sa pisanim ili tiskanim uputstvima za uporabu. The preparation may, if desired, be in the form of a package accompanied by written or printed instructions for use.

Pripravci se pripremaju i oblikuju u skladu sa uobičajenim metodama, kao što su one prikazane u standardnom referentnom tekstu, na primjer British and US Pharamcopoeias, Remington's Pharmaceutical Sciences (Mack Publishing Co.), Martindale The Extra Pharmacopoeia (London, The Pharmaceutical Press) and Harry's Cosmeticology (Leonard Hill Books). The preparations are prepared and formulated according to the usual methods, such as those shown in standard reference text, for example British and US Pharamcopoeias, Remington's Pharmaceutical Sciences (Mack Publishing Co.), Martindale The Extra Pharmacopoeia (London, The Pharmaceutical Press) and Harry's Cosmeticology (Leonard Hill Books).

U skladu s tim, izum osigurava uporabu jednog insulin sensitiser-a, kao što je spoj (I), i osobito u količini od 2 do 12 mg, za proizvodnju lijeka za liječenje hiperglikemije, posebice hiperglikemije na tašte, naznačenu time što je razina glukoze u plazmi u rasponu od povišene normalne do ≤ 126 mg/dl. Accordingly, the invention provides the use of an insulin sensitiser, such as compound (I), and in particular in an amount of 2 to 12 mg, for the production of a drug for the treatment of hyperglycemia, especially fasting hyperglycemia, characterized by a glucose level in plasma ranging from elevated normal to ≤ 126 mg/dl.

Izum također osigurava uporabu jednog insulin sensitiser-a, kao što je spoj (I) i to osobito u količini od 2 do 12 mg, za proizvodnju lijeka za poboljšanje kontrole glikemije u stanjima koja su karakterizirana hiperglikemijom, posebice hiperglikemijom na tašte, s time da se poboljšanje osigurava naznačeno time što je razina glukoze u plazmi u rasponu od povišene normalne do ≤ 126 mg/dl, i stoga odlaže ili sprječava dalje povišenje hiperglikemije. The invention also provides for the use of an insulin sensitiser, such as compound (I), especially in an amount of 2 to 12 mg, for the production of a drug for improving glycemic control in conditions characterized by hyperglycemia, especially fasting hyperglycemia, with improvement is provided by plasma glucose ranging from elevated normal to ≤ 126 mg/dl, and therefore delays or prevents further elevation of hyperglycemia.

U daljem aspektu, izum osigurava uporabu jednog insulin sensitiser-a, kao što je spoj (I) i osobito u količini od 2 do 12 mg, za proizvodnju lijeka za profilaksu hiperglikemije, posebice hiperglikemije na tašte, naznačene time što je razina glukoze u plazmi > 126 mg/dl. In a further aspect, the invention provides the use of an insulin sensitiser, such as compound (I) and in particular in an amount of 2 to 12 mg, for the production of a medicine for the prophylaxis of hyperglycemia, especially fasting hyperglycemia, indicated by the fact that the plasma glucose level > 126 mg/dl.

Posebice ovaj izum osigurava farmaceutski pripravak koji sadrži jedan insulin sensitiser, kao što je spoj (I) i osobito u količini od 2 do 12 mg/dl, i njegov farmaceutski prihvatljiv nosač, za uporabu u liječenju hiperglikemije, osobito hiperglikemije na tašte, naznačene time što je razina glukoze u plazmi u rasponu od povišene normalne do ≤ 126 mg/dl ili za poboljšanje kontrole glikemije u stanjima karakteriziranim hiperglikemijom na tašte, a poboljšanje se osigurava u rasponu hiperglikemije naznačene time što je razina glukoze u plazmi u rasponu od povišene normalne do ≤ 126 mg/dl, i stoga odlaže ili sprječava dalje povišenje hiperglikemije ili za profilaksu hiperglikemije, osobito hiperglikemije na tašte, naznačene time što je razina glukoze u plazmi > 126 mg/dl. In particular, this invention provides a pharmaceutical preparation containing an insulin sensitiser, such as compound (I) and especially in an amount of 2 to 12 mg/dl, and its pharmaceutically acceptable carrier, for use in the treatment of hyperglycemia, especially fasting hyperglycemia, indicated by which is a plasma glucose level in the range from elevated normal to ≤ 126 mg/dl or to improve glycemic control in conditions characterized by fasting hyperglycemia, and the improvement is provided in the hyperglycemia range indicated by a plasma glucose level in the range from elevated normal to ≤ 126 mg/dl, and therefore delays or prevents further elevation of hyperglycemia or for the prophylaxis of hyperglycemia, especially fasting hyperglycemia, indicated by a plasma glucose level > 126 mg/dl.

Nikakvi nepovoljni toksični učinci nisu za očekivati kod pripravaka ili metoda iz ovog izuma u gore spomenutim rasponima doza. No adverse toxic effects are to be expected with the compositions or methods of this invention in the aforementioned dosage ranges.

Claims

1. Metoda za liječenje hiperglikemije naznačena time što je razina glukoze u rasponu od povišene normalne do ≤ 126 mg/dl, a ta metoda obuhvaća primjenu učinkovite ne - toksične i farmaceutski prihvatljive količine jednog insulin sensitiser-a, na sisavcu kojemu je potrebna.1. A method for the treatment of hyperglycemia characterized by the fact that the glucose level is in the range from elevated normal to ≤ 126 mg/dl, and this method comprises the application of an effective non-toxic and pharmaceutically acceptable amount of an insulin sensitiser to a mammal in need thereof.

2. Metoda u skladu sa zahtjevom 1, naznačena time što je hiperglikemija, hiperglikemija na tašte.2. The method according to claim 1, characterized in that the hyperglycemia is hyperglycemia in the mother-in-law.

3. Metoda u skladu sa zahtjevom 2, naznačena time što je hiperglikemija karakterizirana razinom glukoze u plazmi na tašte u rasponu od povišene normalne do ≤ 126 mg/dl i dalje je karakterizirana putem hiperglikemije koja slijedi oralni test tolerancije na glukozu naznačen time što je razina glukoze u plazmi < 140 mg/dl.3. The method according to claim 2, characterized in that the hyperglycemia is characterized by a fasting plasma glucose level ranging from elevated normal to ≤ 126 mg/dl and is further characterized by hyperglycemia following an oral glucose tolerance test characterized in that the level glucose in plasma < 140 mg/dl.

4. Metoda u skladu sa zahtjevom 2, naznačena time što je hiperglikemija karakterizirana razinom glukoze u plazmi na tašte u rasponu od povišene normalne do ≤ 126 mg/dl, i dalje je karakterizirana putem hiperglikemije koja slijedi oralni test tolerancije na glukozu u rasponu od 140 do < 200 mg/dl.4. The method according to claim 2, characterized in that the hyperglycemia is characterized by a fasting plasma glucose level in the range of elevated normal to ≤ 126 mg/dl, further characterized by hyperglycemia following an oral glucose tolerance test in the range of 140 to < 200 mg/dl.

5. Metoda u skladu sa bilo kojim od zahtjeva 1 do 4, naznačena time što je insulin sensitiser tiazolidindionski insulin sensitiser.5. The method according to any one of claims 1 to 4, characterized in that the insulin sensitiser is a thiazolidinedione insulin sensitiser.

6. Metoda u skladu sa bilo kojim od zahtjeva 1 do 5, naznačena time što je insulin sensitizer spoj (I).6. The method according to any one of claims 1 to 5, characterized in that the insulin sensitizer is compound (I).

7. Metoda u skladu sa zahtjevom 6, naznačena time što se dnevno primjenjuje 2 do 12 mg spoja (I).7. The method according to claim 6, characterized in that 2 to 12 mg of compound (I) is administered daily.

8. Metoda u skladu sa bilo kojim od zahtjeva 1 do 4, naznačena time što je insulin sensitiser izabran sa liste koja se sastoji od: (+)-5-[[4-[(3,4-dihidro-6-hidroksi-2,5,7,8-tetrametil-2H-l-benzopiran-2-il)metoks]fenil]metil]-2,4-tiazolidindion (ili troglitazon), 5-[4-[(1-metilcikloheksil)metoksi]benzil]tiazolidin-2,4-dion (ili ciglitazon), 5-[4-[2-(5-etilpiridin-2-il)etoksi]benzil]tiazolidin-2,4-dion (ili pioglitazon ) i 5-[(2-benzil-2,3-dihidrobenzopiran)-5-ilmetil]tiazolidin-2,4-dion (ili englitazon); ili njihovi tautomerni oblici, ili njihove farmaceutski prihvatljive soli, ili njihovi farmaceutski prihvatljivi solvati.8. The method according to any one of claims 1 to 4, characterized in that the insulin sensitiser is selected from the list consisting of: (+)-5-[[4-[(3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2-yl)methoxy]phenyl]methyl]-2 ,4-thiazolidinedione (or troglitazone), 5-[4-[(1-methylcyclohexyl)methoxy]benzyl]thiazolidine-2,4-dione (or ciglitazone), 5-[4-[2-(5-ethylpyridin-2-yl)ethoxy]benzyl]thiazolidine-2,4-dione (or pioglitazone) and 5-[(2-benzyl-2,3-dihydrobenzopyran)-5-ylmethyl]thiazolidin-2,4-dione (or englitazone); or tautomeric forms thereof, or pharmaceutically acceptable salts thereof, or pharmaceutically acceptable solvates thereof.

9. Metoda u skladu sa bilo kojim od zahtjeva 1 do 8, naznačena time što je insulin sensitiser u obliku pripravaka prilagođenih za oralnu primjenu.9. The method according to any one of claims 1 to 8, characterized in that the insulin sensitiser is in the form of preparations adapted for oral administration.

10. Metoda u skladu sa zahtjevom 9, naznačena time što je pripravak u obliku jedinične doze.10. The method according to claim 9, characterized in that the preparation is in the form of a unit dose.

11. Uporaba insulin sensitiser-a za proizvodnju lijeka za liječenje hiperglikemije naznačene time što je razina glukoze u plazmi u rasponu od povišene normalne do ≤ 126 mg/dl.11. Use of an insulin sensitiser for the production of a drug for the treatment of hyperglycemia characterized by a plasma glucose level ranging from elevated normal to ≤ 126 mg/dl.

12. Farmaceutski pripravak koji sadrži jedan insulin sensitiser i farmaceutski prihvatljivog nosača, za uporabu u liječenju hiperglikemije naznačene time što je razina glukoze u plazmi u rasponu od povišene normalne do ≤ 126 mg/dl.12. A pharmaceutical preparation containing an insulin sensitiser and a pharmaceutically acceptable carrier, for use in the treatment of hyperglycemia characterized by a plasma glucose level ranging from elevated normal to ≤ 126 mg/dl.